The colibactin-producing Escherichia coli alters the tumor microenvironment to immunosuppressive lipid overload facilitating colorectal cancer progression and chemoresistance

Nilmara de Oliveira Alves (1, 2) , Guillaume Dalmasso (3) , Darja Nikitina (4, 5, 6) , Amaury Vaysse (7) , Richard Ruez (1, 2) , Lea Ledoux (8) , Thierry Pedron (9, 10) , Emma Bergsten (11) , Olivier Boulard (1, 2) , Lora Autier (1, 2) , Sofian Allam (1, 2) , Laurence Motreff (12) , Pierre Sauvanet (3) , Diane Letourneur (11) , Pragya Kashyap (13) , Johan Gagnière (3) , Denis Pezet (3) , Catherine Godfraind (3) , Michel Salzet (8) , Emmanuel Lemichez (11) , Mathilde Bonnet (3) , Imène Najjar (12) , Christophe Malabat (12) , Marc Monot (12) , Denis Mestivier (14) , Nicolas Barnich (3) , Pankaj Yadav (13) , Isabelle Fournier (8) , Sean Kennedy (4, 5) , Amel Mettouchi (11) , Richard Bonnet (3) , Iradj Sobhani (14, 15) , Mathias Chamaillard (1, 2)

1 SIRIC-ONCOLille - Site de Recherche Intégrée en Cancérologie
2 PHYCELL - Laboratoire de Physiologie Cellulaire : Canaux ioniques, inflammation et cancer - U 1003
3 M2iSH - Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte
4 CNRS - Centre National de la Recherche Scientifique
5 IP - Institut Pasteur [Paris]
6 LSMU - Lithuanian University of health Sciences
7 Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB
8 PRISM - Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U 1192
9 Pathogénie microbienne moléculaire
10 Bactériophage, bactérie, hôte - Bacteriophage, bacterium, host
11 Toxines bactériennes - Bacterial Toxins
12 C2RT - Pôle Biomics
13 Indian Institute of Technology Jodhpur
14 UPEC UP12 - Université Paris-Est Créteil Val-de-Marne - Paris 12
15 CHU Henri Mondor [Créteil]

Intratumoral bacteria flexibly contribute to cellular and molecular tumor heterogeneity for supporting cancer recurrence through poorly understood mechanisms. Using spatial metabolomic profiling technologies and 16SrRNA sequencing, we herein report that right-sided colorectal tumors are predominantly populated with Colibactin-producing Escherichia coli (CoPEC) that are locally establishing a high-glycerophospholipid microenvironment with lowered immunogenicity. It coincided with a reduced infiltration of CD8+ T lymphocytes that produce the cytotoxic cytokines IFN-γ where invading bacteria have been geolocated. Mechanistically, the accumulation of lipid droplets in infected cancer cells relied on the production of colibactin as a measure to limit genotoxic stress to some extent. Such heightened phosphatidylcholine remodeling by the enzyme of the Land’s cycle supplied CoPEC-infected cancer cells with sufficient energy for sustaining cell survival in response to chemotherapies. This accords with the lowered overall survival of colorectal patients at stage III-IV who were colonized by CoPEC when compared to patients at stage I-II. Accordingly, the sensitivity of CoPEC-infected cancer cells to chemotherapies was restored upon treatment with an acyl-CoA synthetase inhibitor. By contrast, such metabolic dysregulation leading to chemoresistance was not observed in human colon cancer cells that were infected with the mutant strain that did not produce colibactin (11G5∆ClbQ). This work revealed that CoPEC locally supports an energy trade-off lipid overload within tumors for lowering tumor immunogenicity. This may pave the way for improving chemoresistance and subsequently outcome of CRC patients who are colonized by CoPEC.

Mots clés: Colibactin-producing Escherichia coli; land’s cycle; lipid droplet; right-sided colorectal cancer

Domaines: Cancer; Hépatologie et Gastroentérologie; Bactériologie

Nilmara de Oliveira Alves, Guillaume Dalmasso, Darja Nikitina, Amaury Vaysse, Richard Ruez, et al.. The colibactin-producing Escherichia coli alters the tumor microenvironment to immunosuppressive lipid overload facilitating colorectal cancer progression and chemoresistance. Gut microbes, 2024, 16 (1), pp.2320291. ⟨10.1080/19490976.2024.2320291⟩. ⟨hal-04542255⟩